1. Field of the Invention
The present invention relates generally to the field of automatic dissolution testing of products whose solubility and dissolution rate properties affect product performance, and more specifically to an improved dissolution cell specially configured to accommodate the rapid and iterative insertion of product specimens into the dissolution medium of the testing system.
The dissolution cell is configured with a plurality of flow channels, each of which may contain a product specimen, and is operable to insert a selected flow channel/product specimen into the dissolution measurement chamber with a minimal impact on the initial conditions established within the testing system.
2. Description of the Prior Art
Dissolution testing of components of industrial products whose solubility and dissolution rate properties affect product performance can be used as a screening and quality control tool. The solubility properties of solid materials can depend on polymorphic crystalline form, crystal habit, crystal shape, particle size and particle size distribution, and state of solvation. A simple and rapidly performed dissolution test can substitute for the determination of these physical properties by more time consuming and expensive methods such as x-ray crystallography, differential thermal analysis, microscopy, etc. The materials are instead determined as to whether they conform to a dissolution rate standard under specified conditions and in relation to a known reference sample of the same material characterized by the above physical properties and possessing the derived dissolution rate and solubility performance.
The broad technique of determining dissolution rate properties is especially of interest in the testing of drug products where the therapeutic performance of drugs is closely related to the drug dissolution properties. Seemingly minor changes in drug product formulation, as well as the inadvertent variation in materials and manufacture that can occur between batches of the same product formulation, can influence the therapeutic performance of drugs. In vivo bioavailability testing of drug products in humans provides the most reliable means of ensuring bioequivalence. However, it is impractical to perform the extensive and expensive human testing that would be routinely required. Large numbers of human subjects would be placed at risk if such studies were conducted. Bioavailability testing in which humans are used as test subjects can be minimized by the development and implementation of in vitro dissolution standards that reflect in vivo drug-product performance. In vitro bioequivalence requirements have been established for some drugs such as digoxin. From among the various chemical and physical tests that can be performed on drug solids in vitro for correlating or predicting a drug product's in vivo bioavailability behavior, dissolution testing is the most sensitive and reliable. The correlative relationships most commonly reported between in vitro dissolution and in vivo bioavailability are of the single-point type: the percentage of the drug dissolved in a given time (or the time it takes to dissolve a given percentage of the drug in vitro) and some univariate characteristic of the drug product's in vivo response versus time profile (such as the peak blood level, the time required to reach the peak or 50% of the peak, or the area under the blood-level curves) are correlated. The selection of in vitro dissolution and in vivo bioavailability parameters for such single-point correlations is frequently arbitrary, and the results can be misleading. Obviously, it would be preferable to predict the entire average blood level, urinary recovery rate, pharmacological-response-time, or drug absorption rate vs. time profile that would be elicited by a drug product in a panel of human subjects rather than merely to correlate univariate characteristics of the dissolution profile with an in vivo bioavailability parameter. In all cases, however, the fidelity of the in vitro dissolution results in correlating and in predicting in vivo drug-product bioavailability depends upon the dissolution-test process variables, such as the dissolution-medium composition, the solubility volume of the medium (sink conditions that determine the extent to which the medium becomes saturated with the drug), and the agitation rates (stirring or flow rates). An improper choice of these process variables (e.g., an excessively high rate of agitation) can mask significant bioavailability differences among drug products. On the other hand, the dissolution test can be overly sensitive in detecting differences that are negligible in vivo. In the former case, using such improper dissolution-test parameters would result in the marketing of therapeutically ineffective drug products. In the latter case, the result would be the discarding of drug products that are entirely satisfactory in terms of in vivo performance. Serious economic losses could result from the use of an overly sensitive in vitro dissolution test for lot-to-lot reproducibility testing of drug products. Therefore, whether the dissolution test is being used as a quality control tool, as an in vivo bioequivalency requirement for multisource generic drug products, or as a substitute for human bioavailability testing during the development of new drug-product formulations, it is imperative that the dissolution test provide predictive results that are biologically relevant.
A detailed description of an automatic dissolution testing system which employs an online microprocessor to continually optimize a set of process variables may be found in a copending application by the same inventor as the present application entitled, "Method and Apparatus for Automatic Dissolution Testing of Products". That application was filed on Apr. 17, 1980 and bears the Ser. No. 141,093.
A significant and troublesome problem inherent in automatic dissolution testing is encountered during the testing of products which have very rapid dissolution rates. This is especially true when the dissolution times of the product specimens involved are short compared to the time constants of the automatic testing system. Thus, the present improved dissolution cell which permits new and useful operating modes is directed to overcoming these problems, and greatly enhances the usefulness of the automatic dissolution testing art.